The use of digitalis glycosides in the treatment of congestive heart failure has long been closely associated with cardiac toxicity. However, preliminary data from our laboratory demonstrate that a cardiac glycoside having a 4-aminosugar attached to digitoxigenin (ASI-222) has a greater positive inotropic action on the heart and a significantly greater therapeutic index (TI) than ouabain (and by implication, all other cardiac glycosides). The objectives of our proposed research are: 1) to establish more firmly and completely this more favorable therapeutic index for ASI-222 by using various preparations from several different species, 2) to establish the optimum structural configuration and site of amino-substitution on a sugar for such a cardiac glycoside which yields the greatest TI, and 3) to determine the basis for this salutary dissociation between efficacy and toxicity. We propose to accomplish our objectives by: 1) establishing therapeutic and toxic effects for ASI-222 and congeners on isolated cat papillary and rabbit atrial muscle and in open-chest dogs. 2) testing certain other glycosides containing either other sugars and/or different amine placements on the sugar (synthesized on contract) on the test systems listed above in quest of the agent with optimum activity (TI), 3) determining the relationships of the therapeutic and toxic effects of ASI-222 and of its congeners to Na, K ions -ATPase activity, certain pharmacokinetic parameters, important cardiac electrical events and to the sympathetic nervous system. Our proposed research should produce a clinically useful cardiac glycoside which has a greater degree of safety than those which are now available.